| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects between the ages of 18 and 70 years with T2DM who are diet and/or exercise treated or receiving stable metformin monotherapy will be recruited |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 7.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052066 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate the dose response and efficacy of 5 doses (2.5 mg, 5 mg, 10 mg, 15 mg
and 20 mg qd) of GW677954 (± metformin) versus placebo (± metformin) on the
reduction of hyperglycemia (assessed by HbA1c) after 16 weeks of dosing in subjects with T2DM |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate temporal changes in PD glycemic parameters, effect on fasting insulin and C-peptide levels, and on measures of insulin resistance through homeostasis model resulting from administering a range of doses of GW677954 (±metformin) in subjects with T2DM.
To investigate the effects of a range of doses of GW677954 (± metformin) versus
placebo (± metformin) on lipid parameters.
To characterize the population PK of GW677954 (± metformin).
To characterize the safety profile of GW677954 (±metformin)
To investigate the effects of a range of doses of GW677954 (± metformin) versus
placebo (± metformin) on biomarkers of fluid retention, cardiovascular risk, systemic
inflammation, and insulin sensitivity.
To characterise the safety and tolerability of GW677954 at doses of 2.5mg, 5mg,10mg and 20mg and compare with that of placebo through assessment of physical examination, vital signs, clinical laboratory tests, ophthalmic assessments and AE reporting.
|
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Subjects with T2DM as defined by the criteria of the ADA and/or recognized by
WHO Expert Committee on the Diagnosis and Classification of Diabetes Mellitus
(American Diabetes Association, 2004), for at least 3 months preceding screening
(see Section 15.3, Appendix 3:, “Diagnosis and Classification of Diabetes Mellitus").
2. To be eligible for Randomization into the trial, a subject must satisfy all of the
following glycemic criteria:
• HbA1c level via central laboratory at the pre-screening visit
• If HbA1c ≥ 8.0% but ≤ 10.0%: subject may proceed to Randomization;
• If HbA1c ≥ 7.8% but < 8.0%, subject not eligible to proceed, but may be retested
once to establish eligibility (or lack thereof). If HbA1c level ≥ 8.0% upon retest,
subject is eligible to proceed; otherwise they should be withdrawn.
If HbA1c < 7.8%, subject not eligible to proceed (no retest allowed).
• FPG level via central laboratory at the pre-screening visit must be < 270 mg/dL (15.0 mmol/L). FPG may be retested within a week to confirm eligibility (or lack thereof).
3. Concurrent T2DM therapy:
• Diet and/or exercise treated: Must not have taken antidiabetic medication for at
least 2 months prior to the pre-screening visit,
OR
• Metformin monotherapy: Subjects entering the study on metformin must be on
the same dose, formulation and regimen of metformin for at least 2 months prior
to the pre-screening visit,
AND
• TZDs and insulin are excluded in the 3 months prior to the Screening visit for all
subjects.
4. Males and females who are 18 to 70 years of age inclusive at the time of Screening.
5. If female, eligible to enter and participate in this study:
• If of non-childbearing potential (i.e., physiologically incapable of becoming
pregnant (tubal ligation), including any female who is post-menopausal [>1 year
without menstrual period]); or,
• If of child-bearing potential, has a negative pregnancy test at Screening (serum),
at Randomization (urine) and:
○ Has a male partner who is sterile prior to the female subject’s entry into
the study and is the sole sexual partner for that female subject, or
○ Uses double-barrier methods of contraception; condoms with the use of
caps (with spermicide) and IUDs are acceptable, or
○ Uses hormonal contraceptives (oral, depots, patches etc) with doublebarrier
methods of contraception as outlined above, or
○ Abstains from sexual intercourse, or
○ Is with a same sex partner and does not participate in bisexual activities
where there is any risk of pregnancy.
6. Body Mass Index (BMI): ≥ 25 and ≤ 40 kg/m2 and weigh at least 50 kg at Screening.
7. If subject is a smoker, must be able to abstain while in clinic at each visit.
8. Subject has given full written informed consent prior to any study related procedures are performed |
|
| E.4 | Principal exclusion criteria |
1. Metabolic Disease including:
• Diagnosis of Type 1 diabetes mellitus
• Uncorrected thyroid dysfunction.
• Significant weight gain or loss within the 3 months prior to Screening.
2. Previous use of insulin for treatment of hyperglycemia within 3 months of screening.
3. History of recent clinically significant cardiovascular disease including:
• History or ECG evidence of prior myocardial infarction within 6 months prior to
Screening.
• Current unstable angina or history of unstable angina in past 6 months.
• Coronary revascularization including percutaneous transluminal coronary
angioplasty (PTCA) or coronary artery bypass graft (CABG) surgery that is either
planned or occurred in the 6 months prior to Screening.
• Clinically significant arrhythmia or valvular heart disease.
• Congestive heart failure (CHF) with New York Heart Association (NYHA) Class
II-IV symptoms (see Section 15.4, Appendix 4).
• Blood pressure > 160/100 mmHg or resting heart rate > 100 bpm.
• Has a QTc interval (Bazett’s) > 440 msec in males and > 450 msec in females at
Screening.
• Clinically significant ECG abnormalities which, in the opinion of the Investigator,
may affect the interpretation of safety data, or which otherwise, contraindicates
participation in a clinical trial with a new chemical entity.
4. History of chronic pancreatitis.
5. Familial hypercholesterolemia.
6. TGs ≥ 800 mg/dL (8.96 mmol/L) at Screening.
7. Serum creatinine at screening > 1.4 mg/dL (124 μmol/L) for women, or > 1.5 mg/dL
(133 μmol/L) for men.
8. Clinically significant anemia defined by hemoglobin concentrations <12.0 g/dL or <
120.0 g/L for males and < 11.0 g/dL or < 110.0 g/L for females.
9. History of significant co-morbid diseases
10. Documented history of hepato-biliary disease including a history of, or positive
laboratory results for hepatitis at Screening, and/or clinically significant hepatic
enzyme elevation including:
• Any one of the following enzymes greater than 2.5 times the upper limit of normal (ULN) value at Screening
11. History of metabolic acidosis, rhabdomyolysis, myalgia, myositis or myopathy after
taking statins or fibrates.
12. Any subject who has withdrawn therapy due to AEs after taking a PPARγ or a
PPARα/γ dual agonist, either marketed (e.g., troglitazone, rosiglitazone or
pioglitazone) or under current or previous clinical investigation.
13. Signs or symptoms of myositis at Screening (or upon 1 repeat test), and/or creatinine phosphokinase (CPK) ≥ 3.0 times ULN
14. Is currently taking or has taken any of the following medications in the 3 months
prior to the pre-screening visit:
• Anti-obesity agents (including fat absorption blocking agents)
• St. John’s Wort
• Warfarin and other oral anticoagulants (excluding aspirin and non-steroidal antiinflammatory
drugs)
• Digoxin
• Oral or injectable corticosteroids (inhaled and intranasal steroids are acceptable)
• Use of antidiabetic agents (other than metformin) in the 2 months prior to the prescreening visit.
• Use of TZDs in the 3 months prior to the pre-screening visit.
• Methotrexate, cyclosporine or monoclonal antibodies (e.g., alemtuzumab,
gemtuzumab ozogamicin, rituximab, trastuzumab, ibritumomab, tioxetan) for
rheumatoid arthritis or psoriasis.
• Atypical antipsychotic medications
• Antiretroviral drugs
• Use of lipid lowering agents within 3 months prior to the pre-screening visit. This
includes statins, fibrates, ezetimibe (Zetia), niacin and bile acid sequestrants.
• Monoamine oxidase inhibitors
15. History of cancer except for basal cell carcinoma or superficial squamous cell carcinoma treated by local excision or cervical cancer in situ treated definitively more than 6 months prior to screening.
16. Women who are lactating, pregnant, or planning to become pregnant.
17. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to any drug
chemically related to the study drug.
18. Known allergy to any of the capsule excipients, or history of drug or other allergy, hypersensitivity to metformin or any of its components (for subjects entering on metformin).
19. Has a history of substance and/or alcohol abuse within the past year as determined by the Investigator at screening or during treatment:
• Unwilling to refrain from the use of illicit drugs and adhere to other protocol stated
restrictions while participating in the study.
• History of alcohol abuse as defined in protocol.
20. Received treatment with a new molecular entity (investigational drug) during the
previous 4 months or participated in any other trial during the previous 3 months, or
has participated in a previous study with GW677954. A new molecular entity is
defined as any compound not in Phase 3. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in fasting HbA1c levels at Week 16 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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